Progress has been made in understanding some genetic aspects of the human hair follicle biology with the discovery of the first two genes directly implicated in human hair growth regulation, both of which result in complete alopecia. One of these genes, the hairless gene, is one of the candidate genes for the regulation of basic hair follicle Function(s). The attenuation of the hairless gene activity results in the progressive shedding of the infantile hair; the consequence is complete hair loss in animals, which represents a phenocopy of the autosomal recessive disorder papular atrichia in humans. Furthermore, the hairless gene product is expressed in the hair follicle, the epidermis, and in the brain. Functional studies indicate that hairless may play a crucial role in maintaining the balance between cell proliferation, differentiation, and apoptosis in the hair follicle and in the interfollicle epidermis. In this proposal, we will investigate the spati-temporal expression of the hairless protein during the skin development and the hair follicle cycling. We also will characterize the cell-types expressing hairless protein in the mouse brain using the different intermediate filament proteins as specific markers. Recently, different groups have generated several knockout mice for nuclear receptors such as the thyroid hormone receptors, the retinoic acid receptor and the vitamin D receptor. Because of the striking similarities of their phenotype with the hairless and rhino mice, we will investigate whether hairless acts as a cofactor for those nuclear receptors. In addition, using different biochemical approaches, we will identify the yet unknown cellular components interacting specifically with hairless protein. Collectively these studies will begin to unravel the physiological function(s) of hairless.